Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disease caused by misexpression of the DUX4 gene in skeletal muscle. DUX4 is a transcription factor, which is normally expressed in the cleavage-stage embryo and regulates gene expression involved in early embryonic development. Recent studies revealed that DUX4 also activates the transcription of repetitive elements such as endogenous retroviruses (ERVs), mammalian apparent long terminal repeat (LTR)-retrotransposons and pericentromeric satellite repeats (Human Satellite II). DUX4-bound ERV sequences also create alternative promoters for genes or long non-coding RNAs, producing fusion transcripts. To further understand transcriptional regulation by DUX4, we performed nanopore long-read direct RNA sequencing (dRNA-seq) of human muscle cells induced by DUX4, because long reads show whole isoforms with greater confidence. We successfully detected differential expression of known DUX4-induced genes and discovered 61 differentially expressed repeat loci, which are near DUX4-ChIP peaks. We also identified 247 gene-ERV fusion transcripts, of which 216 were not reported previously. In addition, long-read dRNA-seq clearly shows that RNA splicing is a common event in DUX4-activated ERV transcripts. Long-read analysis showed non-LTR transposons including Alu elements are also transcribed from LTRs. Our findings revealed further complexity of DUX4-induced ERV transcripts. This catalogue of DUX4-activated repetitive elements may provide useful information to elucidate the pathology of FSHD. Also, our results indicate that nanopore dRNA-seq has complementary strengths to conventional short-read complementary DNA sequencing.An important aspect of the rehabilitation of burn patients is social participation, including daily activities and work. Detailed information on long-term activity impairment and employment is scarce. Therefore, we investigated activity impairment, work status, and work productivity loss in adults 5-7 year following burn injuries, and investigated associations with burn-specific health-related quality of life (HRQL) domains. Adult participants completed the Work Productivity and Activity Impairment General Health questionnaire and the Burn Specific Health Scale-brief (BSHS-B) 5-7 year post-burn. https://www.selleckchem.com/products/osmi-1.html Outcomes were compared between participants with mild/intermediate and severe burns (&gt;20% total body surface area burned). Seventy-six (36%) of the 213 participants experienced some degree of activity impairment due to burn-related problems 5-7 years post-burn. Seventy percent of the population was employed; 12% of them experienced work productivity loss due to burn-related problems. Nineteen percent reported changes in their work situation (partly) because of the burn injury. A higher proportion of participants with severe burns had activity impairments (56% vs 29%; p=0.001) and work productivity loss (26% vs 8%; p less then 0.001) compared to participants with mild/intermediate burns. Activity impairment and work productivity loss were both associated with burn-related work problems and lower mood, measured with the BSHS-B. In conclusion, a substantial part of the study population experienced activity impairment and work productivity loss, was unemployed, and/or reported changes in their work situation due to their injury. Particularly patients with severe burns reported productivity loss and had lower employment rates. This subscribes the importance of addressing work-related functioning in the rehabilitation of burn patients.Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency.
To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes.
Double-blind, randomized, placebo-controlled 12-month longitudinal study.
Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study.
Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range.
Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates.
Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P?=?0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P?=?0.042), while parathyroid hormone increased in AN-IGF-1+ (P?=?0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups.
We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.
We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.We describe five patients with syncope caused by a complete atrioventricular block (AVB) while they were bending forward, not rising after bending, and aim to describe the occurrence and the association between bending forward and AVB.
In two patients, bending forward was the exclusive trigger for syncope, while in the remaining three, other postural changes (sitting down, standing up, and exertion) could also provoke syncope. Complete AVB as the cause of syncope was documented using ECG monitoring in two cases and an implantable loop recorder in the other three. Ectopic beats without preceding sinus slowing occurred before syncope in four cases. Two cases had a left bundle branch block. All patients responded favourably to cardiac pacing.
This is the first case series on complete AVB provoked by bending forward. Syncope during bending forward should suggest a search for an AVB. Arguments in favour of a vagal mechanism were syncope triggered by bending forward, and that other triggers could also evoke syncope.